Dipeptidyl peptidase IV (DPP-IV), a member of the prolyl peptidase family, cleaves certain dipeptides at the penultimate position from the amino termini of the proteins. It contributes to rapid degradation of glucagon-like peptide-1 (GLP-1), a gut hormone produced by intestinal endocrine L-cells in response to food ingestion. GLP-1 in turn inhibits glucagon secretion and stimulates glucose-dependent insulin release from the pancreas (Zander M, et al. Lancet 2002, 359: 824-830). It has been shown that inhibiting DPP-IV resulted in enhanced insulin secretion, reduced plasma glucose levels, and improved pancreatic β-cell function (Pederson R. A., et al. Diabetes 1998, 47: 1253-1258; and Ahren B, et al. Diabetes Care 2002, 25: 869-875). DPP-IV inhibitors are therefore potential drug candidates for Type II diabetes.
Recent studies indicate that DPP-IV inhibitors were potential inhibitors of dipeptidyl peptidase VIII (DPP-VIII), another member of the prolyl peptidase family, and that inhibition of DPP-VIII resulted in side effects, e.g., toxicity and thrombocytopenia (Diabetes, 2005, 54: 2988-2994). Thus, DPP-IV inhibitors, as Type II diabetes drug candidates, preferably possess little or no inhibitory activity against DPP-VIII.